Robust chronic convulsive seizures, high frequency oscillations, and human seizure onset patterns in an intrahippocampal kainic acid model in mice

Abstract

Intrahippocampal kainic acid (IHKA) has been widely implemented to simulate temporal lobe epilepsy (TLE), but evidence of robust seizures is usually limited. To resolve this ambiguity, we slightly modified previous methods and employed continuous wideband video-EEG monitoring from 4 recording sites to best detect and characterize chronic epilepsy outcomes in both male and female mice. We found many more convulsive seizures than most studies have reported. Mortality was low. Analysis of convulsive seizures at 2-4 and 10-12 wks post-IHKA showed a robust frequency (2-4 per day on average) and duration (typically 20-30 sec) at each time. Comparison of the two timepoints showed that seizure burden became more severe in approximately 50% of the animals. We show that almost all convulsive seizures could be characterized as either low-voltage fast or hypersynchronous onset seizures, which has not been reported in a mouse model of epilepsy and is important because these seizure types are found in humans. In addition, we report that high frequency oscillations (>250 Hz) occur, resembling findings from IHKA in rats and TLE patients. Pathology in the hippocampus at the site of IHKA injection was similar to mesial temporal lobe sclerosis and reduced contralaterally. In summary, our methods produce a model of TLE in mice with robust convulsive seizures, and there is variable progression. HFOs are robust also, and seizures have onset patterns and pathology like human TLE.

Differential vulnerability of neuronal subpopulations of the subiculum in a mouse model for mesial temporal lobe epilepsy

“…1C,C1). In agreement with previous observations 30 , it was impossible to determine the exact onset site whereas the post-ictal depression started with a delay on the contralateral side (Fig. 1C2).…”

Epilepsy-associated increase in gonadotropin-releasing hormone neuron firing in diestrous female mice is independent of chronic seizure burden severity

“…A limitation of the present study is that seizures were only recorded ipsilateral to the site of KA injection in the right dorsal hippocampus. Although seizures in the IHKA model primarily arise in the ipsilateral hippocampal region and many epileptiform events stay focally confined to the hippocampus (Lévesque and Avoli, 2013; Twele et al, 2017), seizure activity can spread and generalize to other brain regions (Sheybani et al, 2018), in some cases producing convulsive seizures (Bui et al, 2018; Lisgaras and Scharfman, 2022; Zeidler et al, 2018). However, other rodent models of TLE with primarily focal seizures also show prominent estrous cycle disruption (Amado et al, 1987; Christian et al, 2020; Edwards et al, 1999; Fawley et al, 2012; Scharfman et al, 2008).…”

“…Therefore, seizure generalization does not appear to be an absolute requirement for the development of comorbid reproductive endocrine dysfunction, but it remains to be determined whether there is a relationship between the rate of seizure generalization and downstream GnRH neuron and HPG axis dysfunction. Nevertheless, as both electrographic and convulsive seizure activity are consistently detected in the injected hippocampus in IHKA mice (Bouilleret et al, 1999; Lisgaras and Scharfman, 2022; Riban et al, 2002; Sheybani et al, 2018), depth EEG recording in the ipsilateral hippocampus as performed here enables recording of the vast majority of seizures in this model. Therefore, it is unlikely that the present results represent an underestimate of overall seizure burden in these mice.…”

Optimization of closed-loop electrical stimulation enables robust cerebellar-directed seizure control

“…Ictal spike detection was individualized for each mouse based on several features, including minimum and maximum inter-spike distance, spike width, and spike amplitude (similar to Armstrong et al 67 ). Additionally, epileptic spikes were often associated with brief high frequency oscillations (HFOs) 69 ; therefore, in some instances, an HFO detector (500-1500 Hz; using the same features as spike detection; spike width, amplitude, etc.) was used to improve spike discrimination.…”